title: Indistinguishable synaptic pharmacodynamics of the N-methyl-D-aspartate receptor channel blockers memantine and ketamine.
abstract: Memantine and ketamine, voltage- and activation-dependent channel blockers of N-methyl-d-aspartate (NMDA) receptors (NMDARs), have enjoyed a recent resurgence in clinical interest. Steady-state pharmacodynamic differences between these blockers have been reported, but it is unclear whether the compounds differentially affect dynamic physiologic signaling. In this study, we explored nonequilibrium conditions relevant to synaptic transmission in hippocampal networks in dissociated culture and hippocampal slices. Equimolar memantine and ketamine had indistinguishable effects on the following measures: steady-state NMDA currents, NMDAR excitatory postsynaptic current (EPSC) decay kinetics, progressive EPSC inhibition during repetitive stimulation, and extrasynaptic NMDAR inhibition. Therapeutic drug efficacy and tolerability of memantine have been attributed to fast kinetics and strong voltage dependence. However, pulse depolarization in drug presence revealed a surprisingly slow and similar time course of equilibration for the two compounds, although memantine produced a more prominent fast component (62% versus 48%) of re-equilibration. Simulations predicted that low gating efficacy underlies the slow voltage-dependent relief from block. This prediction was empirically supported by faster voltage-dependent blocker re-equilibration with several experimental manipulations of gating efficacy. Excitatory postsynaptic potential-like voltage commands produced drug differences only with large, prolonged depolarizations unlikely to be attained physiologically. In fact, we found no difference between drugs on measures of spontaneous network activity or acute effects on plasticity in hippocampal slices. Despite indistinguishable synaptic pharmacodynamics, ketamine provided significantly greater neuroprotection from damage induced by oxygen glucose deprivation, consistent with the idea that under extreme depolarizing conditions, the biophysical difference between drugs becomes detectable. We conclude that despite subtle differences in voltage dependence, during physiologic activity, blocker pharmacodynamics are largely indistinguishable and largely voltage independent.
authors.affiliation: Graduate Program in Neuroscience (C.M.E.), Washington University, and Departments of Psychiatry (C.M.E., A.M.T., Y.I., C.F.Z., S.M.), Neurology (L.N.E.), Anatomy and Neurobiology (C.F.Z., S.M.), and Taylor Family Institute for Innovative Psychiatric Research (Y.I., C.F.Z., S.M.), Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Emnett
authors.forename: Lawrence N
authors.initials: LN
authors.lastname: Eisenman
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Taylor
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Izumi
authors.forename: Charles F
authors.initials: CF
authors.lastname: Zorumski
authors.forename: Steven
authors.initials: S
authors.lastname: Mennerick
mesh_terms: D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000172:deficiency; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D005947:Glucose; D010100:Oxygen; D008559:Memantine